LncRNA4474 inhibits renal fibrosis by regulating hepatocyte nuclear factor-1β through miR-615 modulation

Abstract

ABSTRACT Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in the development and progression of renal fibrosis. lncRNAs can regulate target messenger RNAs (mRNAs) by competitively binding to miRNAs. However, research on lncRNA–miRNA–mRNA interactions remains inadequate. Therefore, the aim of the present study was to investigate the possible function of lncRNA–miRNA–mRNA interactions in chronic renal fibrosis. The relationships among the expression levels of lncRNA4474, miR-615, and hepatocyte nuclear factor-1β (HNF-1β) mRNAs were determined through RNA sequencing. The biological roles of lncRNA4474, miR-615, and HNF-1β in renal fibrosis were investigated with gain-of-function and loss-of-function experiments. Results showed that miR-615 expression increased in unilateral ureteral obstruction rats, accompanied by decreased lncRNA4474 and HNF-1β mRNA expression. The overexpression of HNF-1β attenuated the development of chronic renal fibrosis, whereas HNF-1β knockdown promoted the development. Increase in HNF-1β expression downregulated and upregulated the expression levels of miR-615 and lncRNA4474, respectively, thereby attenuating renal fibrosis progression. Furthermore, lncRNA4474 promoted the expression of HNF-1β by inhibiting miR-615 expression, whereas miR-615 regulated the expression of HNF-1β and thus activated the Wnt signaling pathway. This study demonstrated that the overexpression of lncRNA4474 may attenuate fibrosis progression, accompanied by the downregulation of miR-615 and upregulation of HNF-1β. Hence, this study provides novel information that can be useful in the early diagnosis and treatment of renal fibrosis.